Ectopic expression of RET results in microphthalmia and tumors in the retinal pigment epithelium

The retinal pigment epithelium (RPE) is essential for eye development by in teracting with the overlaying neuroepithelium, Regulatory sequences of the gene encoding for tyrosinase-related protein I (TRP-I), linked to the lacZ reporter gene, lead to strong and specific beta-galactosidase expression in the RPE, We asked how the oncogene ret would affect this epithelial cell t ype during mouse development, We used the TRP-I promoter to express ret in the developing RPE, and obtained transgenic mouse lines, which showed mild to severe microphthalmia, During development, the RPE changed to a stratifi ed epithelium with reduced or absent pigmentation from E10.5 onward. In add ition, proliferation of RPE cells and tumor formation were observed from E1 2.5 onward. These early events prevent closure of choroid fissure and lead to microphthalmia and secondary malformations after birth. We conclude that ret transgene expression in the RPE prevents normal differentiation of thi s epithelial layer and induces proliferation and tumor formation. The appea rance of the microphthalmic phenotype underlines the requirement of a norma lly developed RPE for eye development. Int. (C) 1999 Wiley-Liss, Inc.